19-nor-16-oxy-allopregnanes



United States Patent Patented May 8, 1962 3,033,749 19-NOR 16-0XY-ALLOPREGNANES Albert Wettstein, Basel, Robert Neher, Binningen, and Ernst Vischcr and Peter Wieland, Basel, Switzerland, assignors to Ciba Pharmaceutical Products Inc., Summit, N J. No Drawing. Fiied Dec. 17, 1958, Ser. No. 780,929 Claims priority, application Switzerland Dec. 20, 1957 3 Claims. (Cl. 167- 65) The present invention provides 20-oxo-l9-nor-allopregnane compounds of the formula |--H I Lon in which X indicates hydrogen or a methyl group, Y either two hydrogen atoms or one free, esterified or etherified hydroxyl group together with one hydrogen atom, or an oxo group, Z indicates hydrogen or halogen and R is hydrogen or an acyl, ether or glucoside radical. The compounds concerned are therefore substituted or unsubstituted 20-oxo-l9-nor-allopregnane-3 8: l6oc-di0lS, their esters, ethers and glucosides, which may have a double bond in 1:2- and/or 9(l1)- or llzl2-position.

The ester radicals are, for example, such of saturated or unsaturated aliphatic or cycloaliphatic, of aromatic or heterocyclic carboxylic acids, for example of fatty acids, particularly lower fatty acids, such as formic acid, acetic acid, propionic acid, butyric acids, lactic acid, valeric acids, such as n-valeric acid or trimethylacetic acid, diethylacetic acid, caproic acids, such as fl-trimethylpropionic acid, oenanthic acids, caprylic acids, pelargonic acids, capric acids, undecylic acids, eg undecylenic acid, lauric acid, myristic acid, palmitic acid or stearic acids, eg. oleic acid, crotonic acid, undecanic acid; halogenated fatty acids, particularly halogenated lower fatty acids, such as chloracetic acid, trifluoracetic acid, trichloroacetic acid; carbamic acids, such as N-alkyl, especially N-lower alkyl carbamic acids, for example, N-methyl carbamic acid, N-ethyl carbamic acid, also N-aryl (especially monocyclic aryl) carbamic acids, for example N-phenyl carbamic acid etc.; cycloaliphatic (especially those containing or 6 carbon atoms in the cyclic nucleus) carboxylic acids, such as cyclohexyl carboxylic acid, cyclohexenyl carboxylic acid, cyclopentyl carboxylic acid, cyclopentenyl carboxylic acid; aliphatic-cycloaliphatic (especially those containing 5 or 6 carbon atoms in the cyclic nucleus) lower fatty acids, such as cyclopentyl acetic acids, cyclohexyl acetic acid, cyclopentyl propionic acid, cyclohexyl propionic acid, cyclohexenyl propionic acid; benzoic acid and corresponding substituted acids, such as p-amino-benzoic acid, chloro-benzoic acids; aryl substituted fatty acids (especially lower fatty acids substituted by monocyclic aryl residues) such as phenyl acetic acid, phenyl propionic acid, phenyl butyric acid, tolyl propionic acid, etc.; phenoxyalkanoic acids (especially lower alkanoic), such as phenoxyacetic acid, 4-tertiary-butyl-phenoxyacetic acid, 3-phenoxy-propionic acid, 4-phenoxy-butyric acid, halo-substituted phenoxy alkanoic acids, such as para-chlorophenoxyacetic acid, 2:4- dichlorophenoxyacetic acid, furane-Z-carboxylic acid, lower alkyl substituted furane-Z-carboxylic acids, such as 5-tertiary butyl-furane-Z-carboxylic acid, halo-substituted furane-Z-carboxylic acids, such as S-bromoor chlorofurane-Z-carboxylic acid, and N-heterocyclic carboxylic acids, such as nicotinic acid and isonicotinic acid; aliphatic, aromatic or cycloaliphatic dicarboxylic acids, such as oxalic acid, succinic acid, maleic acid, glutaric acid, dimethyl-glutaric acid, pimelic acid, acetone-dicarboxylic acid, phthalic acid, tetrahydrophthalic acid, hexahydrophthalic acid, endomethylene-tetrahydrophthalic acid, endomethylene-hexahydrophthalic acid, endoxy hexahydrophthalic acid, endoxy-tetrahydrophthalic acid, camphon'c acid, cyclopropane-dicarboxylic acid, cyclobutane-dicarboxylic acid, diglycolic acid, ethylene-bisglycolic acid, polyethylene-bisglycolic acid, quinolinic acid, cinchomeronic acid, furane-dicarboxylic acid, dihydroand tetrahydrofurane-dicarboxylic acid, thiodiglycolic acid, and the polyethylene-glycol-monoalkyl ether semiesters of the above dicarboxylic acids, of ketocarboxylic acids, such as B-keto-carboxylic acids, for example of acetoacetic acid, propionylacetic acid, butyrylacetic acid or caprionoylacetic acid, of amino acids, such as diethylamino-acetic acid etc. Instead of carboxylic acid radicals there may be present those of sulfonic acids, such as methane-sulfonic acid or toluene-sulfonic acid, and of inorganic acids, such as phosphoric acids or sulfuric acids.

As ether radicals are concerned especially such of lower monoor polyhydric aliphatic or cycloaliphatic alcohols, such as methanol, ethanol, ethylene or propylene glycols, cyclohexanol, tetrahydropyranol or lower araliphatic alcohols such as benzyl alcohol, or of phenols, preferably mouocyclic phenols. In the glucosides the sugar radicals are such of monosaccharides, such as glucose, galactose, mannose or arabinose, or of polysaccharides, such as maltose, lactose or other galactosido-glucoses and lactosido-glucoses. Of the halogen derivatives the fluorine and chlorine derivatives may be especially mentioned.

The products of this invention have a sodium eliminating effect and can be used therapeutically for the restoration of a disturbed sodium equilibrium, especially in cases of retention of sodium, especially oedemae and circulatory afl'ections including high blood pressure.

The invention also provides processes for the manufacture of the new 20-oxo-l9-nor-allopregnane-3fl:16adiol compounds. These processes include the following:

(a) In compounds of the formula CH-OH X in which X, Y, Z and R have the above significance, a

3 l6a-hydroxyl is introduced with removal of the double bond, or e Compounds of the formula in which X, Y, Z and R have the above significance, are hydroxylated in 16oz-POSiti0n by microbiological methods known per se, or

(d) In compounds of the formula Y la CM in which X, Y, Z and R have the above significance, the l6azl7u-epoxide group is split up with formation of a la-hydroxyl group, or

(e) In compounds of the formula in which X, Y, Z and R have the above significance, and

which contain in 4:5'-, :6- or 5:10-position a double bond, this latter double bond is reduced.

According to process (a) the starting materials are dehydrogenated in 20-position, for which purpose a series of known processes can be used,'for example oxidation by means of compounds of hexavalent chromium, such as chromium trioxide in glacial acetic acid or chromium trioxide-pyridine complex, potassitun dichromate, or also oxy-benzyl alcohol, p-tolyl-carbinol, diphenylor triphenyl-carbinol, in a neutral medium or with the action of alkaline or acid catalysts, for example of alkali car-' bonates or hydroxides, mineral acids, sulfonic acids, boron trifluoride and so on, and,':if desired, the resulting l6a-O-etherssplit reductively to the Ida-ole. As reducing agents are primarilysuitable catalytically activated hydrogen, for example in fthe presence of palladium icatalystspsuch as palladium-calcium carbonate, or also complex metalhhydrides, such as lithium-aluminum or' lithium-boron, hyd -ide.' In, the application of the latter: method it is'advantageous toprotectthe ZQ-oxo-group by ketalization, for example with ethylene, 1:2-propylene or 1:3-propylene glycol, using an acid catalyst, such as p-toluene sulfonic acid. After the reduction, the 20-ketal is split up to the ZO-ketone by careful acid hydrolysis.

According to process (0) the starting materials are hydroxylated in 16u-position by methods of a known type, in which, for example, they are incubated aerobically together with living microorganisms that are capable of introducing a hydroxyl group into the cposition. It is possible however to use such microbial enzymes, which are separated to a greater or lesser extent from the culture filtrate or from the mycelium and consequently to work in the absence of living microorganisms. The l6a-hydroxylating microorganisms, for example strains of the genus Streptomyces such as Strepton zyces roseochromogenus, or strains of the species, Dialymella vodakii and Pestalotia funera, are cultivated by methods of known type, for example in still cultures or in submerged, agitated cultures, advantageously containing assimilable carbon, especially carbohydrates. The simplest process for use in practice is described below but there is no intention to limit the invention to this process: The organisms are cultivated in apparatus and under conditions similar to those known in the so-called deep tank process for antibiotic manufacture. After development of the cultures, the specified starting materials are added in fine dispersion or solution, for example in methanol, acetone or ethylene glycol and incubation continued. Finally the mycelium is separated and the filtrate and/or the mycelium mass extracted, and from the extract the reaction products are isolated in a manner known per se, for example by partition processes, adsorption, chromatography, crystallization, conversion into functional derivatives such as Girard compounds and the like.

The splitting up of the 16cc; 17a-cpoxide by process (d) can be carried out, for example, by either of the following two methods. One consists in that the 161x117- epoxide is treated with chromyl chloride or acetate, whereby with reductive opening of the epoxide ring the 16m-hydr0xyl compound is obtained directly. According to the other method the 16st: 17a-epoxide is reacted with an aryl hydrazine, advantageously in the presence of an acid catalyst, for example p-toluene sulfonic acid, the resulting A -l6a-hydroxy-20-arylazo-pregnene reduced by means of zinc and glacial acetic acid in pyridine solution to the 16u-hydroxy-20-aryl hydrazone and then the 20*oxo group liberated by hydrolysis with pyroracemic acid and/ or p-hydroXy-benzaldehyde.

According to process (e), in the starting materials the 4;5-, 516-, or 5zl0-double bond is reduced. As reducing agent is primarily suitable catalytically activated hydrogen, for example in the presence of nickel, platinum or palladium catalysts, such as Raney nickel, platinum oxide or palladium-calcium carbonate. The reduction is car ried out in a neutral or acid medium, for example in alcohols, such as methanol or ethanol, or organic acids, such as glacial acetic acid. The resulting Bfl-hydroxyl9-nor-allopregnane compound is separated from the hydrogenation mixture in a manner known per se, for example by a partition process, adsorption, chromatography or crystallization.

The starting materials for t'nc'preseut process, which in addition to the substituents specified and indicated in the formulae'can contain a double bond in 1: 2- and/or 9:11- or llzl2-position, are obtained by methods known per se. The starting materials used in process (0) and (d) are obtained from those used in process (b) by hydrogenation or epoxylation of the l6 l7-double bond.

The products containing free hydroxyl and/or 0x0 7 groups can be converted by methods of known type into their functional derivatives such as esters, ethers, enol osters, enol ethers, acetals, their corresponding" thio derivatives, for example thio ethers, thio vacetals and esters of 'thio acids, or also hydrazones and oximes.

In the esters and enol esters the acid radicals are those of the acids specified above. In the ethers, enol ethers and acetals or the corresponding thio-derivatives, the radicals of the aliphatic, alicyclic, araliphatic, aromatic or heterocyclic series can be concerned. Such radicals include, for example, alkyl or alkylene groups, such as methyl, ethyl or ethylene, aralkyl groups such as benzyl or dior triphenylmethyl, tetrahydropyranyl groups or sugar radicals, such as those of glucose, galactose, mannose, arabinose, maltose, lactose or other galactosido-glucoses or lactosido-glucoses.

For the etherification and acetylization there are used, for example, reactive esters of corresponding alcohols, especially those of the hydrohalic acids, organic sulfonic acids or orthoformic acid, or also free alcohols, silicon tetraalkyl and the like. According to the agents used the reaction is conducted in the presence of acid or basic condensing agents or catalysts, for example sulfonic acids, mineral acids, such as hydrohalic acids, or sulfuric acids, or organic bases, especially tertiary amines. For the production of the glucoside derivatives are suitable any acylhalogenoses, such as the acetochloro-, acetobromo-, acetoiodoor acetofluoro-derivatives of mono-, dior trisaccharides, for example of glucoses, galactose, maltose, lactose and other galactosido-glucoses and lactosidoglucoses.

The production of the thio-acetals and thio-enol ethers is carried out, for example, by treatment with mercaptocompounds. Thio enol eithers and sulfur-acetals are preferably produced by reaction of resulting acylic thioacetals with mercaptide-forming heavy metal derivatives. As mercapto compounds are used especially alkyl mercaptans, for example methyl, ethyl or benzyl mercap tan or ethylene dimercaptan and the like in the presence of acid catalysts, for example hydrochloric acid, sulfuric acid, toluene sulfonic acid, zinc chloride or pyridine hydrochloride. Mercaptide-forming heavy metal derivatives include especially oxides or inorganic or organic salts, for example chlorides, nitrates, carbonates, acetates, propionates or benzoates of mercury, silver cadmium, copper, lead, bismuth, cobalt or nickel. The reaction is advantageously carried out with exclusion of water and if desired in the presence of organic or inorganic acid-binding agents, for example pyridine, colidine or carbonates, such as alkali metal, alkaline earth metal or heavy metal carbonates. The splitting out of mercaptan from the acyclic thio-acetals can also be achieved by thermal action.

By suitable selection of the reaction conditions and the quantity of the agents used it is possible to subject the hydroxyl or oxo groups present to complete or only to partial functional conversion, for example esterification or etherification.

In resulting compounds functionally converted hydroxyl or oxo groups can be converted into free groups. In this manner especially in the case of polysubstituted derivatives, the functionally converted groups can also be liberated in part. This takes place, for example, by chemical or enzymatic hydrolysis, for example using acid or basic agents, by transesterification, reacetalization or, especially in the case of araliphatic acid or alcohol radicals, also by hydrogenation. From oxygen-sulfur acetals, preferably by means of heavy metal salts, such as mercuric chloride, in the presence of basic agents, for example cadmium carbonate, the cyclic semi-acetals can be obtained. From the only partially converted, such as esterified or etherified, derivatives, obtained in this manner or also directly, by subsequent functional conversion, for example esterification or etherification, polysubstituted derivatives can be produced, especially mixed ester or ethers or ester-ethers. By suitable selection of the reaction conditions it is also possible by the use of the above specified agents to obtain the free compounds from the partially or completely converted derivatives.

The invention also comprises any modification of the process in which only part of the process stages are carried 6 out and/or in which'the'se stages are effected in a difierent sequence, or in which a compound obtainable as an intermediate at any stage of the complete process is used as starting material and the remaining step or steps are carried out.

The present invention also provides preparations for application in human or veterinary medicine and which contain the specified 20-oxo-l9-nor-allopregnan-3/3:16adiol compounds and a solid or liquid medicament carrier. The preparations are produced by methods known per se, for example using pharmaceutical, organic or inorganic carrier materials suitable for parenteral, enteral or local administration. Such substances are concerned as do not react with the products of the present process, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, gelatine, lactose, starch, magnesium stearate, talc, petroleum jelly, cholesterol or other medicament carriers. Preparations are especially concerned for parenteral administration, preferably solutions, primarily oleaginous'or aqueous solutions, or also suspensions, emulsions or implantation tablets for enteral administration in a corresponding manner tablets or dragees can be produced and for local administration salves 'of'creams. If desired, the preparations can be sterilized or can be subjected to the addition of auxiliary substances such as preserving, stabilizing, wetting or emulsifying-agents, salts for variation of the osmotic pressure or buffer substances. The following examples illustrate the invention:

Example 1 mg. of 19-nor-16m: l7a-epoxy-allopregnane-36-01-20- one are dissolved in 12 cc. of glacial acetic acid and shaken with 20 equivalent of chromous acetate, suspended in 4 cc. of water, in an evacuated vessel for 15 hours at 20 C. After pouring water into the vessel, extraction is carried out 3 times with 50 cc. of etherchlorofor-m (3:1), the solution washed with diluted hydrochloric acid, dilute sodium carbonate solution and, until neutral with water and after drying over sodium sulfate evaporated under vacuum. The residue is taken up in methanolchloroform (1: 1) and the solution produced concentrated under vacuum until crystallization commences. After treating with acetone the whole is allowed to stand at 10 C. for 1 hour followed by filtration with suction and washing with acetone. After recrystallization from methanol, 19-nor-allopregnane-3 3:l6a-diol-20-one is obtained.

The 19 nor-16a: 17 a-epoxy-allopregnan-e-3 fi-ol-20-one used as starting material is prepared in the manner known per se from l9-nor-diosgenin by hydrogenation to the 19-nor-tigogenin, side chain degradation of the A -19-norallopregnene-3 S-ol-20 one and epoxylation of the latter compound by means of alkaline hydrogen peroxide.

Example 2 40 mg. of A -l9-nor-pregnene-3B:l6a-diol-20-one are hydrogenated in 15 cc. of ethanol with 30 mg. of palladium-calcium carbonate (10% Pd) at 25 C. under slight excess pressure until 1 mol of hydrogen has been taken up.

After distillation of the filtered solution under vacuum, the residue is chromatographed on two grams of silica gel with 15% water content. The fractions obtained with chloroform-acetone (1:1) are recrystallized from methanol and in this manner yield the 19-nor-allopregnane- 3/3: l6a.-diol-20-one.

The A -l9-nor-pregnene-3 3:l6n-diol-20-one used as starting material can be obtained, for example, by reduc tion of 19-nor-progesterone-ZO-mono-ketal by means of sodium-boron hydride, ketal splitting and l6a-hydroxylation (for example using Didymella vodakii).

Example 3 In two conical flasks each of 500 cc. capacity are placed cc. each of a nutrient solution containing in 1 liter of tap water the following additions: 10 grams of crude glucose, grams of peptone, 3 grams of meat extract (Oxo Lab Lemco), 5 grams of sodium chloride and grams of calcium carbonate, The flasks are inoculated with Streptomyces sp. A 7747 and shaken for 48 hours at 2 6 C. Then under sterile conditions there is added to the well developed cultures in each case a solution of mg. of 19anor-allopregnane-3B-ol-ZO-one in 0.5 cc. of acetone and shaking is continued at the same temperature. After 48 hours the mycelium is separated off and the combined culture filtrate is extracted three times with 50 cc. of ethyl acetate. The extracts are washed with a little Water, com.- bined, dried over sodium sulfate and evaporated under vacuum. The resulting residue contains together with 19- nor-allopregnane-3fl-ol-20-one and a few secondary prod? ucts for the most part 19-nor-a1lopregnane-3fi: l6a-diol-20- one, which can be isolated in pure form by means of preparative paper chromatography.

The starting material can be obtained in the manner known per se by reduction of the double bond and the 0x0 group of 19enor-progesteronea20-monoketal and ketal splitting.

Example 4 As described in Example'3 two cc, cultures are pr uced o S p yces o o h om e s nd as escribed incubation thereof is then carried out in each case together with 30 mg. of 19-nor-allopregnane-3fi-ol-20-one; Working up yields an extraction residue containing 19- nor-allopregnane-3fi:16u-diol-20-one. The latter is isolated in pure form by means of preparative paper chromatography.

What is claimed is:

1. 19-nor-allopregnane-3 ,8: l6ot-diol-20-one.

2. A member of the group consisting of a 3-monoester, a 16-monoester and a 3,16-diester of 19-nor-allopregnane- 3fizl6a-diol-20-one, the ester radical being derived from a member selected from the group consisting of a lower aliphatic acid, a lower alicyclic acid containing 5 to 6 carbon atoms in the carbocyclic portion of the molecule, a monocyclic carbocyclic aromatic acid and a lower araliphatic acid.

3. A pharmaceutical composition comprising a member of the group consisting of 19-nor-a1lopregnane-3Bfl6udiol-ZO-one and an ester thereof, the ester radical being derived from a member selected from the group consisting of a lower aliphatic acid, a lower alicyclic acid, containing 5 to 6 carbon atoms in the carbocyclic portion of the molecule, a monocyclic carbocyclic aromatic acid and a lower araliphatic acid, together with a pharmaceutical excipient in an amount ranging from 0.001 to 10%.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,033,749 May 84 1962 Albert Wettstein et a1.

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 3, lines 4 to 14 the formula should appear as shown below instead of as in the patent:

Signed and sealed this 19th day of May 1964.

(SEAL) Attest:

ERNEST We SWIDER EDWARD J T BRENNER Attesting Officer Commi ss oner of Pat ente 

2. A MEMBER OF THE GROUP CONSISTING OF A 3-MONOESTER, A 16-MONOESTER AND A 3,16-DIESTER OF 19-NOR-ALLOPREGNANE3B:16A-DIOL-20-ONE, THE ESTER RADICAL BEING DERIVED FROM A MEMBER SELECTED FROM THE GROUP CONSISTING OF A LOWER ALIPHATIC ACID A LOWER ALICYCLIC ACID CONTAINING 5 TO 6 CARBON ATOMS IN THE CATBOCYCLIC PORTION OF THE MOLECULE, A MONOCYCLIC CARBOCYCLIC AROMATIC ACID AND A LOWER ARALIPHATIC ACID. 